This invention relates to novel pyrrolopyrimidine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Compounds that are useful in the treatment of hyperproliferative diseases are referred to the following patent applications: PCT international patent application number PCT/IB97/00675 (filed Jun. 11, 1997), U.S. provisional patent application No. 60/041,846 (filed Apr. 9, 1997), U.S. provisional patent application No. 60/031,862 (filed Nov. 27, 1996), U.S. provisional patent application No. 60/028,881 (filed Oct. 17, 1996), PCT international patent application number PCT/IB97/00584 (filed May 22, 1997), U.S. patent application Ser. No. 08/653,786 (filed May 28, 1996), PCT international patent application publication number WO 96/40142 (published Dec. 19, 1996), PCT international patent application publication number WO 97/13771 (published Apr. 17, 1997), PCT international patent application publication number WO 95/23141 (published Aug. 31, 1995) and United States patent application having attorney reference number PC9882B (filed Feb. 10, 2000). Each of the foregoing United States and PCT international patent applications is incorporated herein by reference in its entirety.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residue in proteins and hence to influence cell proliferation. The foregoing tyrosine kinases may be classified as growth factor receptor (e.g. TIE-2, TrkA, EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. It is known that such kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. It has also been shown that epidermal growth factor receptor (EGFR) is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
Tie-2 (TEK) is a member of a recently discovered family of endothelial cell specific receptor tyrosine kinases which is involved in critical angiogenic processes, such as vessel branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian receptor tyrosine kinase for which both agonist ligand(s) (e.g., Angiopoietin1 (“Ang1”), which stimulates receptor autophosphorylation and signal transduction), and antagonist ligand(s) (e.g., Angiopoietin2 (“Ang2”)), have been identified. Knock-out and transgenic manipulation of the expression of Tie-2 and its ligands indicates tight spatial and temporal control of Tie-2 signaling is essential for the proper development of new vasculature. The current model suggests that stimulation of Tie-2 kinase by the Ang1 ligand is directly involved in the branching, sprouting and outgrowth of new vessels, and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and inducing quiescence. The absence of Ang1 stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation by Ang2, which is produced at high levels at sites of vascular regression, may cause a loss in vascular structure and matrix contacts resulting in endothelial cell death, especially in the absence of growth/survival stimuli.
The situation is however more complex, since at least two additional Tie-2 ligands (Ang3 and Ang4) have recently been reported, and the capacity for heterooligomerization of the various agonistic and antagonistic angiopoietins, thereby modifying their activity, has been demonstrated. Targeting Tie-2 ligand-receptor interactions as an antiangiogenic therapeutic approach is thus less favored and a kinase inhibitory strategy preferred.
The soluble extracellular domain of Tie-2 (“ExTek”) can act to disrupt the establishment of tumor vasculature in a breast tumor xenograft and lung metastasis models and in tumor-cell mediated ocular neovasculatization. By adenoviral infection, the in vivo production of mg/ml levels ExTek in rodents may be achieved for 7-10 days with no adverse side effects. These results suggest that disruption of Tie-2 signaling pathways in normal healthy animals may be well tolerated. These Tie-2 inhibitory responses to ExTek may be a consequence sequestration of ligand(s) and/or generation of a nonproductive heterodimer with full-length Tie-2.
Recently, significant upregulation of Tie-2 expression has been found within the vascular synovial pannus of arthritic joints of humans, consistent with a role in the inappropriate neovascularization. This finding suggests that Tie-2 plays a role in the progression of rheumatoid arthritis. Point mutations producing constitutively activated forms of Tie-2 have been identified in association with human venous malformation disorders. Tie-2 inhibitors are, therefore, useful in treating such disorders, and in other situations of inappropriate neovascularization. The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of receptor and non-receptor tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. Agents, such as the compounds of the present invention, that are capable of binding to or modulating the Tie-2 receptor may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
It is known that growth factors such as the neurotrophin family activate receptor tyrosine kinases such as trks. The neurotrophin family of growth factors includes nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). These basic proteins are approximately 120 amino acids in length, share approximately 50% sequence homology, and are highly conserved among mammalian species (Issackson et al., FEBS Lett. 285:260-64, 1991). NGF was the first growth factor discovered and remains the best characterized neurotrophin. NGF is required for normal development of sensory and sympathetic neurons and for normal function of these cells in adult life (Levi-Montalcini, Annu. Rev. Neurosci. 5:341-362, 1982; Yankner et al., Annu. Rev. Biochem 51:845-868,1982).
Neurotrophin binding and activation of a set of high affinity receptors (trks) is necessary and sufficient to mediate most of the biological effects of the neurotrophins. The trks are transmembrane proteins that contain an extracellular ligand binding domain, a transmembrane sequence, and a cytoplasmic tyrosine kinase domain. The trks comprise a family of structurally related proteins with preferential binding specificities for the individual neurotrophins. TrkA, which is sometimes referred to as trk, is a high-affinity receptor for NGF, but it can also mediate biological responses to NT-3 under particular conditions (Kaplan et al. Science 252:554-558, 1991; Klein et al., Cell 65, 189-197, 1991; Cordon-Cardo et al., Cell 66:173-183, 1991). TrkB binds and mediates functions of BDNF, NT-3, and NT4/5 (Klein et al. Cell 66:395-403, 1991; Squinto et al., Cell 65:885-893, 1991; Klein et al. Neuron 8:947-956, 1992). TrkC is relatively specific for NT-3 (Lamballe et al., Cell 66:967-979, 1991).
The Trk family of receptor tyrosine kinases is frequently expressed in lung, breast, pancreatic and prostate cancers. See, Endocrinol. 141: 118, 2000; Cancer Res., 59: 2395, 1999; Clin. Cancer Res. 5: 2205, 1999; and Oncogene 19: 3032, 2000. The tyrosine kinas activity of Trk is believed to promote the unregulated activation of cell proliferation machinery. Recent pre-clinical data suggests that Trk inhibitors suppress the growth of breast, pancreatic and prostate tumor xenografts. Furthermore, it is believed that Trk inhibition may be tolerated in cancer patients. It is also believed by those in the art that inhibitors of either TrkA or TrkB kinases have utility against some of the most common cancers, such as brain, melanoma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological, and thyroid cancer. It is further believed that additional therapeutic uses of Trk inhibitors include pain, neurapthay and obesity.